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Original article
Significance of apical cavity obliteration in apical hypertrophic cardiomyopathy
  1. Hyungseop Kim,
  2. Jung-Ho Park,
  3. Ki-Bum Won,
  4. Hyuck-Jun Yoon,
  5. Hyoung-Seob Park,
  6. Yun-Kyeong Cho,
  7. Chang-Wook Nam,
  8. Seongwook Han,
  9. Seung-Ho Hur,
  10. Yoon-Nyun Kim,
  11. Kwon-Bae Kim
  1. Division of Cardiology, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
  1. Correspondence to Dr Hyungseop Kim, Department of Internal Medicine, Keimyung University Dongsan Medical Center, 56 Dalseong-Ro, Jung-Gu, Daegu 700-712, Republic of Korea; khyungseop{at}dsmc.or.kr

Abstract

Objective Apical hypertrophic cardiomyopathy (HCM) is characterised by apical systolic obliteration and is associated with atrial fibrillation (AF), stroke, heart failure (HF), and mortality. We investigated whether apical obliteration of the left ventricular (LV) cavity could have an unfavourable impact on the clinical course of apical HCM.

Methods 188 patients with apical HCM (114 males, median age 67 years) were identified retrospectively from January 2008 to December 2010. The rate of apical obliteration was defined as the net obliteration to end-diastolic apical cap thickness, and the ratio of obliteration to cavity was defined as the end-systolic obliteration to cavity height. Events were defined as a composite of new onset of AF, stroke, HF, and cardiovascular (CV) death.

Results There were 43 clinical events (19 AFs, 11 HFs, 9 strokes, and 4 deaths) during a follow-up of median 4.4 years. The events patients were older, had larger left atrial volume index (LAVI), lower late diastolic mitral annular tissue Doppler velocity (a′), and higher LV end-diastolic pressure (E/e′). They had greater apical thickness and obliteration, smaller systolic cavity height, higher rate of obliteration, and higher ratio of obliteration to cavity; events were significantly higher (54%) in the upper tertiles of the ratio of obliteration to cavity. Age, E/e′, a′, LAVI, apical thickness, rate of obliteration, and ratio of obliteration to cavity were associated with events. On multivariable analysis, the ratio of obliteration to cavity remained a significant predictor.

Conclusions The ratio of obliteration to cavity could provide useful information to predict the occurrence of adverse events in apical HCM.

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Introduction

Hypertrophic cardiomyopathy (HCM) is considered a risk factor for heart failure (HF) and arrhythmic cardiovascular (CV) events, and is related to sudden cardiac death.1 ,2 Compared with septal HCM, apical HCM is frequently encountered in populations in Asian countries, including Japan and Korea, and is believed to follow a benign course.3 ,4

Apical HCM is a variant form of HCM, and primarily involves myocardial hypertrophy in the apical segments or the apical true cap region. Its natural course is clinically different from that of septal HCM. Apical HCM does not interfere with blood flow through the left ventricular (LV) outflow tract, nor does it contribute to increased LV intra-cavity pressure gradient and, thus, rarely causes symptoms of HF. However, the prevalence of atrial fibrillation (AF) is high, up to 15–20% among HCM patients, and these patients experience more frequent strokes than non-HCM patients.5 In addition, high incidences of HF and cardiac mortality are observed in apical HCM, and there is substantial evidence that apical HCM worsens HF symptoms.6 It seems likely that those CV outcomes are related to LV systolic or diastolic dysfunction and apical remodelling.7–9 Specifically, echocardiography shows apical LV cavity systolic obliteration, which causes markedly high systolic pressure loading on the LV cavity, and this systolic obliteration could result in pathologic conditions such as ischaemia or electrocardiographic changes.10

Despite the high incidence of CV events, there are few or limited studies on the causal relationship between apical HCM and clinical outcomes,4–6 and little is known about the significance of the apical systolic obliteration caused by apical HCM or its relationship to clinical outcomes. Thus, this study aimed to identify the echocardiographic predictors of the occurrence of clinical CV events, focusing on systolic obliteration of the LV cavity in patients with apical HCM.

Methods

Study population

This is a retrospective, longitudinal observational study. Patients with apical HCM were identified retrospectively from January 2008 to December 2010 in a single tertiary university hospital, and their echocardiography reports were evaluated. Patients were classified into two groups according to clinical events. Inclusion criteria were: (1) age >18 years, (2) normal sinus rhythm, and (3) apical HCM documented by echocardiography, with a myocardial thickness >15 mm in apical segments or the true apical cap region. Patients with arrhythmia including AF, prosthetic valves, more than moderate valvular disorders, renal failure requiring replacement therapy, and inadequate echocardiographic or clinical data were excluded. This study was reviewed and approved by the ethical institutional review board and conducted in accordance with good clinical practice and the Declaration of Helsinki.

Echocardiography

In all patients, conventional echocardiographic data were collected, including tissue Doppler imaging, according to the recommendations of the American Society of Echocardiography.11 Left atrium (LA) volume was calculated by area–length methods, and apical thickness of the myocardium was reviewed in three views (apical two-/three-/four-chamber views) by two echocardiography experts (M Y Kim and J H Jeon). The patients were enrolled if the myocardial thickness in the apical segment or apical cap was >15 mm in apical chamber views. End-diastolic maximal hypertrophic thickness in the apical segments and the true apical cap thickness were measured, but it was difficult to measure an end-diastolic LV cavity height from the true apex because of vertical axis distortion caused by the hypertrophied segment (figure 1). Instead, the end-systolic maximal height of the LV cavity was measured together with the end-systolic apical obliteration length from the true apex in order to define clearly the severity of LV cavity obliteration. Therefore, the rate of apical obliteration was defined as the net obliteration to end-diastolic apical cap thickness, and the ratio of obliteration to cavity was defined as the end-systolic obliteration to cavity height (figures 1 and 2). Each view and the average of three apical chamber views were used for the analysis.

Figure 1

In end-diastole, the apical cap thickness (C) was measured in the cap region and the maximal hypertrophic thickness (T) was obtained in any apical segments (shaded region). Apical obliteration length (L) and the height of the left ventricular cavity (H) were measured in end-systole.

Figure 2

Examples of ratio of obliteration to cavity. Two representative cases with obliteration length less than and more than height of left ventricular cavity. (A and B) Apical cap thickness (C) is measured with a long axis length of 1.82 cm at end-diastole, and obliteration length (L) and height (H) measurements are 2.07 and 6.91 cm, respectively at end-systole; thus, in this case, the ratio of obliteration to cavity is defined as L/H=2.07/6.91=0.3. (C and D) In another case, severe apical obliteration compared with the height of the left ventricular cavity is demonstrated at end-systole; accordingly, the ratio of obliteration to cavity is calculated as 1.48. The same alignment or axis between apical obliteration and left ventricular cavity is not always achieved, and care is taken to obtain an optimal long axis dimension for obliteration length and height.

Composite of clinical events

Clinical events were defined as a composite of the occurrences of new onset of AF, stroke, HF, and CV death during follow-up. Follow-up information was gathered during visits to the outpatient clinic, by reviewing medical records or with telephone contacts.

Statistics

All statistical analyses were performed with the Statistical Package for Social Science (SPSS for Windows V.13.0, SPSS Inc, Chicago, Illinois, USA) and STATA software (Stata/IC for Windows V.10.0, StataCorp LP, College Station, Texas, USA). Continuous data are presented as mean±SD if the data were normally distributed, and as median (IQR) if not. Differences were compared by Student's t test if normally distributed and by Mann-Whitney U test if not. Categorical variables are presented as numbers or percentages, and χ2 test was used to compare categorical variables between groups. Box-and-whisker plots were generated to depict the distribution of data for ratio of obliteration to cavity. Cox analysis was used to identify univariable and multivariable predictors of clinical events. Univariable predictors were selected and entered in multivariable analysis to adjust significant confounders and to evaluate the predictor's ability for the occurrence of clinical events. Clinical events-free using the Kaplan-Meier method was determined and adjusted for significant confounders identified in univariable Cox analysis, using the overall Mantel-Cox log rank statistic. p Values were two-sided, and a value of p<0.05 was considered statistically significant.

Results

Baseline characteristics of study patients

The whole study group comprised 188 patients, and their median age was 67.0 years (60.6% were male); 13.8% of the patients had a medical history of stroke, 2.7% had a history of HF, and 16.5% had a history of ischaemic heart disease. During a median follow-up of 4.4 (IQR 1.7–5.6) years, clinical events were observed in 43 patients in the entire study patients (table 1). Of the 188 patients in this study, 9 (5%) had stroke, 4 (2%) had CV death, 11 (6%) had worsening HF, and 19 (10%) had new onset of AF, giving a composite total of 43 (23%) who experienced any of these events. The patients who experienced events during follow-up were older and more often female than the patients who experienced no events. However, no significant differences in blood pressure, laboratory parameters, and medication usage were observed.

Table 1

Clinical and baseline characteristics of study patients

Echocardiographic findings

Tables 2 and 3 summarise the echocardiographic characteristics of the patients. Overall, the patients with events had more enlarged LAVI, lower late diastolic tissue Doppler velocity of the mitral annulus (a′), and higher E/e′ ratios than those without events.

Table 2

Echocardiographic findings of study patients according to clinical events

Table 3

Echocardiographic findings according to clinical events

Apical lateral (37.8%) and septal segments (24.5%) were frequently involved in apical hypertrophy, whereas hypertrophy in the true apical cap segment showed a prevalence of only 7.5%. Patients in the events group had greater thickness in the hypertrophic segments. With respect to the LV apical thickness, the systolic and diastolic thickness of the myocardium were much more increased and the height of the LV cavity was shorter in the events group than in the event-free group. Accordingly, the ratio of obliteration to cavity had a significant association with clinical events, as did the rate of apical obliteration, in each of the three chamber views and their average. Figure 3A, B shows that the ratio of obliteration to cavity was higher in the events group, and the frequency distribution of clinical events was significantly different by the tertile of ratio of obliteration to cavity (p<0.001).

Figure 3

(A) Distribution of ratio of obliteration to cavity according to the occurrence of clinical events. (B) Percentage of clinical events during the follow-up period according to the tertile of the ratio of obliteration to cavity. (C) Kaplan-Meier event-free curves according to half of the ratio of systolic obliteration to cavity in study patients to evaluate the clinical events. (D) After Kaplan-Meier event-free curves were adjusted for significant univariable confounders, including rate of obliteration, a similar result was observed in study patients: the number of patients at risk during follow-up are not applicable in the adjusted Kaplan-Meier analysis.

Prognosis

Table 4 shows the detailed results of the univariable and multivariable Cox regression models. In the univariable Cox regression model of the study patients, the maximal apical thickness of the hypertrophic segment, the rate of obliteration, the ratio of obliteration to cavity, LAVI, E/e′ ratio, and a′ were significantly associated with clinical events, along with age. On multivariable analysis, the ratio of obliteration to cavity was still an independent predictor of clinical events. According to the Kaplan-Meier event-free curve, a ratio of obliteration to cavity of over 0.5 (obliteration length more than half of LV cavity height) was found to be strongly related to the occurrence of AF, stroke, HF, and CV death (figure 3C). Even after adjusting for all the univariables listed in table 4, there was virtually no change in the event-free survival curve (figure 3D).

Table 4

Univariable and multivariable Cox analysis for clinical events

Discussion

Although septal HCM usually has a poor prognosis, there have been few data on the prognosis of apical HCM, and the impact of apical obliteration of the LV cavity has not been investigated. In apical HCM, hypertrophic apical thickness, per se, did not provide any prognostic information in the current study, but the patients with prominent apical obliteration against the LV cavity had a poor prognosis. Rather than apical thickness, the severity of the obliteration of the LV cavity would imply both LV hypertrophic mass effect and LV intra-cavity pressure, leading to diastolic LV dysfunction and resulting in increased LAVI. Thus, we agree that LA size is an indicator of the chronicity of LA or LV diastolic dysfunction, and LAVI could be an important prognostic factor for AF, stroke, or CV events.

In non-apical phenotypes of HCM such as the septal type, the haemodynamic disturbance caused by mid or septal hypertrophy causes increased symptoms during exercise or activity. In contrast, it is uncertain whether apical HCM causes the haemodynamic problems related to decreased stroke volume or cardiac output. In the current study, without markedly haemodynamic disturbances, a′ was found to be significantly decreased in the events group, but the systolic tissue Doppler velocity of the mitral annulus did not differ between the two groups. Therefore, LV diastolic dysfunction could play a key role in the worsening of symptoms or the occurrence of CV events.

In addition, the decreased LV cavity volume caused by apical hypertrophy was related to increased LV diastolic pressure in the present study. With regards to the impact of LV structural changes on LV diastolic dysfunction, LV volume and mass in HCM have been demonstrated to influence diastolic function more than in healthy controls.12 Our findings concur with the observed mechanism of diastolic dysfunction in HF with normal ejection fraction or hypertensive heart disease.13 ,14 As apical hypertrophy progresses to result in obliteration of the LV cavity, maladaptive physiology would be expected in response to increased LV end-diastolic pressure, decreased end-diastolic volume, or decreased stroke volume. These changes would contribute to diastolic HF, provide an arrhythmic substrate, and increase the likelihood of AF. Therefore, the reduced LV cavity with LA enlargement could reflect the severity of diastolic dysfunction and predict poor prognosis, particularly in apical HCM.

The prevalence of AF is higher in apical HCM than in other types, although an exact explanation for this has not been suggested.4 In our study, AF occurrence was related to diastolic LV dysfunction, as reflected by the decreased a′, increased LAVI, or high E/e′ ratio. These findings were also correlated with the severity of the ratio of LV apical obliteration to cavity (data not shown), primarily contributing to clinical events more than any other factors. Accordingly, LV diastolic dysfunction was noted along with the higher incidence of AF and clinical events, and the magnitude of LV dysfunction was related to the LV structural abnormality or hypertrophy, which is characteristic of HCM.15–17 Therefore, the extent of LV wall hypertrophy could contribute to the occurrence of AF—the greater the extent of hypertrophied myopathy, the worse the LA dysfunction or volume.

The LV apex in hypertrophied myocardium frequently shows prominent and deep recesses, which could be the cause of embedded micro-thrombi, similar to the trabeculation in non-compaction cardiomyopathy.18–20 Unfortunately, there were no data on whether the myocardial contraction surface in all apical directions could be completely contacted and obliterated during the systolic phase. The small slot or space between non-contacted or non-obliterated hypertrophied myocardium could be a possible site of LV thrombus or micro-emboli, as is seen in non-compaction cardiomyopathy. In the light of these findings, it is natural to suspect that LV apical obliteration during systolic contraction could be an important risk factor for stroke.21

Interestingly, an increase in LV obliteration did not solely give a predictability of prognosis for events in the current study. This finding could underscore the importance of the size of the residual LV cavity. It is not certain whether myocardial hypertrophy progresses in only one segment focally or progresses diffusely from the apex up to the mid-ventricle. When there is complete obliteration, such as in diffuse apical to mid-ventricular HCM, LV systolic and diastolic function are easily impaired, including myocardial tissue velocity and trans-mitral inflow.10 ,22 Therefore, the obliteration rate could be primarily involved in AF occurrence during the early stage and may be the first manifestation of CV disease. However, apical hypertrophy is an ongoing process and causes cardiac function to deteriorate later on; the effect of obliteration on CV events could strengthen gradually as the LV cavity size decreases. These findings are relevant to the ever-increasing adverse events identified during the long-term follow-up in the event-free survival analysis. Hypertrophy confined to a single segment, meanwhile, does not seem to contribute to small LV cavity size or volume because it does not cause heavy obliteration of the LV cavity. However, there is a need for further evidence that a small LV cavity is related to poor prognosis, although it reduces stroke volume.

Limitations

This was a retrospective study. We did not measure LV volume by three-dimensional or cardiac MRI but did measure LV ejection fraction by two-dimensional echocardiography. However, the purpose of the present study was to assess the relationship between obliteration length and cavity size; thus, this novel method seems to be sufficient to evaluate the events. Second, the current study population was not compared with normal healthy subjects or patients with other types of HCM. Finally, contrast echocardiography or cardiac MRI were not performed to detect LV apical pouch or deep trabeculation, which could be related to the occurrence of LV thrombus or clinical CV events. Therefore, the actual incidence of apical aneurysm in HCM, which would be associated with CV morbidity or mortality, was not assessed from the current analysis, although its development has been frequently described as an important complication.23

Clinical implications

Apical HCM is frequently encountered, and the prevalence of AF with apical HCM is higher than with any other type of HCM. This has been regarded as a benign entity and has not attracted much attention. However, considering the high occurrence of AF, stroke, or CV events in this study, apical HCM is not benign and must be one of the risk factors for AF. It should be noted that the effects of apical obliteration on the LV cavity could worsen LV or LA function and may have contributed to the occurrence of clinical events. In particular, in patients with >0.5 ratio of obliteration to LV cavity (obliteration length more than half of cavity height), careful attention and follow-up should be required to prevent adverse CV events.

Conclusion

Apical HCM demonstrated an unfavourable prognosis in patients with more advanced LV obliteration and was not as benign as expected. The ratio of apical obliteration to LV cavity could provide useful information for predicting the occurrence of AF, stroke, HF and CV death.

Key messages

What is already known on this subject?

  • Apical hypertrophic cardiomyopathy (HCM) has been regarded as a more benign entity than septal HCM.

  • While many patients with apical HCM experience cardiovascular adverse events, the effect of apical systolic obliteration on clinical events has not been evaluated.

What might this study add?

  • We found that the ratio of left ventricular systolic apical obliteration to cavity was related to clinical events such as atrial fibrillation, stroke, heart failure, and cardiovascular death.

How might this impact on clinical practice?

  • Our study's results could help clinicians identify an echocardiographic predictor for the risk stratification of clinical adverse events in patients with apical HCM.

Acknowledgments

The authors wish to thank Mi-Young Kim and Jin-Hwa Jeon for gathering the data of all the patients.

References

Footnotes

  • Contributors HK, Y-KC, HJY and H-SP designed and proposed the protocol of the study. J-HP, K-BW and HK collected the data. J-HP and HK prepared and reviewed the echocardiographic data. HK conducted statistical analysis. SH and S-HH interpreted the results. HK drafted, wrote and revised the manuscript. C-WN, Y-NK and K-BK read and approved the manuscript.

  • Competing interests None declared.

  • Ethics approval Keimyung University Dongsan Medical Center Ethics Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.